Interleukin 13 (IL-13)-mediated allergic inflammation is a hallmark of a number of diseases including asthma, atopic dermatitis, and eosinophilic esophagitis (EoE). IL-13 induces robust, cell-specific changes in gene expression and a majority of IL-13-mediated transcriptional and pathological changes are signal transducer and activator of transcription 6 (STAT6) dependent. For example, in a murine model of EoE induced by IL-13 delivery into the lungs, eosinophilic infiltration and epithelial hyperplasia in the esophagus occur in a STAT6-dependent manner. Likewise, in human intestinal, airway, and esophageal epithelial cells, induction of the eosinophil-specific chemokine (C-C Motif) ligand 26 (CCL26 also referred to as eotaxin-3) by IL-13 requires STAT6 expression. To date, nearly all targets of IL-13 have been signaling molecules and/or soluble mediators of inflammation.
NGF was originally described as a critical factor for the survival and maintenance of sympathetic and sensory neurons, yet NGF is also considered a biomarker of asthmatic inflammation, with increased levels correlating with the severity of the disease. Early growth response protein 1 (EGR1), a central transcriptional target of NGF, has a key role in IL-13-induced inflammation, fibrosis, alveolar remodeling and cytokine response. Neurotrophin tyrosine kinase receptor 1 (NTRK1) is a high affinity receptor for NGF. However, a connection between NTRK1 and these EGR1-associated inflammatory and/or remodeling pathways has not been established.
Asthma is a common chronic inflammatory disease of the airways thought to be caused by a combination of genetic and environmental factors. It is clinically classified according to the frequency of symptoms, forced expiratory volume in one second (FEV1), and peak expiratory flow rate. Treatment options include inhaled short-acting beta-2 agonists, e.g., salbutamol, for acute symptoms, and oral or inhaled corticosteroids.
Atopic dermatitis, also called atopic eczema, is a type of inflammation of the skin. The cause is not known but believed to involve genetics, immune system dysfunction, environmental exposures, and skin permeability problems. Atopic dermatitis affects about 20% of people at some point in their lives and is more common in younger children.
Eosinophilic esophagitis (EoE) is considered to be a chronic immune system disease. Although it was identified only during the last twenty years, it is now considered a major cause of digestive system (gastrointestinal) illness. In EoE, eosinophils (a type of white blood cell) build up in the lining of the esophagus. This buildup, which may be a reaction to foods, allergens or acid reflux, can inflame and/or injure the esophageal tissue. Damaged esophageal tissue can lead to difficulty swallowing or lead to other complications. Symptoms include difficulty swallowing (dysphagia), food impaction, chest pain that is often centrally located and does not respond to antacids, persistent heartburn, upper abdominal pain, lack of response to gastroesophageal reflux disease (GERD) medication, and backflow of undigested food (regurgitation).
Current clinical standards for diagnosis of EoE include (i) endoscopy to inspect the lining of the esophagus for inflammation and swelling, horizontal rings, vertical furrows, narrowing (strictures) and white spots; (ii) biopsy of esophageal tissue with one biopsy showing more than 15 eosinophils per high power field in patients using a proton pump inhibitor (PPI) for approximately 8 weeks.
Treatment for EoE that is not responsive to PPIs includes an orally administered topical steroid, such as fluticasone or budesonide. Where topical steroids prove ineffective, prednisone may be prescribed